Ubiquitin-like 1-activating enzyme E1B (UBLE1B) also known asSUMO-activating enzyme subunit 2 (SAE2) is anenzyme that in humans is encoded by theUBA2gene.[5]
Posttranslational modification of proteins by the addition of the small proteinSUMO (seeSUMO1), orsumoylation, regulates protein structure and intracellular localization.SAE1 and UBA2 form aheterodimer that functions as a SUMO-activating enzyme for the sumoylation of proteins.[5][6]
The UBA2cDNA fragment 2683 bp long and encodes a peptide of 640 amino acids.[6] The predicted protein sequence is more analogous to yeast UBA2 (35% identity) than human UBA3 orE1 (inubiquitin pathway). The UBA gene is located on chromosome 19.[7]
Uba2subunit is 640 aa residues long with a molecular weight of 72 kDa.[8] It consists of threedomains: anadenylation domain (containing adenylation active site), a catalytic Cys domain (containing the catalytic Cys173 residue participated inthioester bond formation), and aubiquitin-like domain.SUMO-1 binds on Uba2 between the catalytic Cys domain and UbL domain.[9]
SUMO activating enzyme (E1, heterodimer of SAE1 and UBA2) catalyzes the reaction of activatingSUMO-1 and transferring it toUbc9 (the only known E2 forSUMOylation). The reaction happens in three steps: adenylation, thioester bond formation, and SUMO transfer to E2. First, the carboxyl group of SUMO C-terminal glycine residue attacks ATP, forming SUMO-AMP andpyrophosphate. Next, the thiol group of a catalytic cysteine in the UBA2 active site attacks SUMO-AMP, forming a high energy thioester bond between UBA2 and the C-terminal glycine of SUMO and releasing AMP. Finally, SUMO is transferred to an E2 cysteine, forming another thioester bond.[9][10][11]
Ubiquitin tag has a well understood role of directing protein towards degradation by proteasome.[12] The role SUMO molecules play are more complicated and much less well understood. SUMOylation consequences include altering substrate affinity for other proteins or with DNA, changing substrate localization, and blocking ubiquitin binding (which prevents substrate degradation). For some proteins, SUMOylation doesn’t seem to have a function.[10][13]
Transcription factorNF-kB in unstimulated cells is inactivated by IkBainhibitor protein binding. The activation of NF-kB is achieved by ubiquitination and subsequent degradation of IkBa. SUMOylation of IkBa has a strong inhibitory effect on NF-kB-dependent transcription. This may be a mechanism for cell to regulate the number of NF-kB available for transcriptional activation.[14]
Transcription factorp53 is atumor suppressor acting by activating genes involved incell cycle regulation andapoptosis. Its level is regulated bymdm2-dependent ubiquitination. SUMOylation of p53 (at a distinct lysine residue from ubiquitin modification sites) preventsproteasome degradation and acts as an additional regulator to p53 response.[15]
Studies of yeastbudding andfission have revealed that SUMOylation may be important in cell cycle regulation.[16] During a cell cycle, the UBA2 concentration doesn't undergo substantial change while SAE1 level shows dramatic fluctuation, suggesting regulation of SAE1 expression rather than UBA2 might be a way for cell to regulate SUMOylation. However, at time points when SAE1 levels are low, little evidence of UBA2-containing protein complexes are found other than SAE1-UBA2 heterodimer. One possible explanation would be that these complexes exist only for a short period of time, thus not obvious in cell extracts. UBA2 expression is found in most organs including the brain, lung and heart, indicating probable existence of SUMOylation pathway in these organs. An elevated level of UBA2 (as well as all other enzyme components of the pathway) is found in testis, suggesting possible role for UBA2 inmeiosis orspermatogenesis. Inside the nucleus, UBA2 is distributed throughoutnuclei but not found innucleoli, suggesting SUMOylation may occur primarily in nuclei. Cytoplasmic existence of SAE 1 and UBA2 is also possible and is responsible for conjugation of cytoplasmic substrates.[17]
^Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M (October 2005). "Towards a proteome-scale map of the human protein-protein interaction network".Nature.437 (7062):1173–8.Bibcode:2005Natur.437.1173R.doi:10.1038/nature04209.PMID16189514.S2CID4427026.
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^Tatham MH, Kim S, Yu B, Jaffray E, Song J, Zheng J, Rodriguez MS, Hay RT, Chen Y (August 2003). "Role of an N-terminal site of Ubc9 in SUMO-1, -2, and -3 binding and conjugation".Biochemistry.42 (33):9959–69.doi:10.1021/bi0345283.PMID12924945.
Stelzl U, Worm U, Lalowski M, Haenig C, Brembeck FH, Goehler H, Stroedicke M, Zenkner M, Schoenherr A, Koeppen S, Timm J, Mintzlaff S, Abraham C, Bock N, Kietzmann S, Goedde A, Toksöz E, Droege A, Krobitsch S, Korn B, Birchmeier W, Lehrach H, Wanker EE (2005). "A human protein-protein interaction network: a resource for annotating the proteome".Cell.122 (6):957–68.doi:10.1016/j.cell.2005.08.029.hdl:11858/00-001M-0000-0010-8592-0.PMID16169070.S2CID8235923.
Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M (2005). "Towards a proteome-scale map of the human protein-protein interaction network".Nature.437 (7062):1173–8.Bibcode:2005Natur.437.1173R.doi:10.1038/nature04209.PMID16189514.S2CID4427026.
Lemos TA, Kobarg J (2006). "CGI-55 interacts with nuclear proteins and co-localizes to p80-coilin positive-coiled bodies in the nucleus".Cell Biochem. Biophys.44 (3):463–74.doi:10.1385/CBB:44:3:463.PMID16679534.S2CID24544907.
Tatham MH, Kim S, Yu B, Jaffray E, Song J, Zheng J, Rodriguez MS, Hay RT, Chen Y (2003). "Role of an N-terminal site of Ubc9 in SUMO-1, -2, and -3 binding and conjugation".Biochemistry.42 (33):9959–69.doi:10.1021/bi0345283.PMID12924945.
